Four stages after stress reactions

1 Levitsky A. P., Malinovskii V. О., Yuzkiv Ya. S., Pavlenko K. V., Selivanskaya I. О., Lapinska A. P. Four stages after stress reactions. Journal of Education, Health and Sport. 2025;86:67246. eISSN 2391-8306. https://dx.doi.org/10.12775/JEHS.2025.86.67246 https://apcz.umk.pl/JEHS/article/view/67246 https://zenodo.org/records/17849597 The journal has had 40 points in Minister of Science and Higher Education of Poland parametric evaluation. Annex to the announcement of the Minister of Education and Science of 05.01.2024 No. 32318. Has a Journal's Unique Identifier: 201159. Scientific disciplines assigned: Physical culture sciences (Field of medical and health sciences); Health Sciences (Field of medical and health sciences). Punkty Ministerialne 40 punktów. Załącznik do komunikatu Ministra Nauki i Szkolnictwa Wyższego z dnia 05.01.2024 Lp. 32318. Posiada Unikatowy Identyfikator Czasopisma: 201159. Przypisane dyscypliny naukowe: Nauki o kulturze fizycznej (Dziedzina nauk medycznych i nauk o zdrowiu); Nauki o zdrowiu (Dziedzina nauk medycznych i nauk o zdrowiu).© The Authors 2025; This article is published with open access at Licensee Open Journal Systems of Nicolaus Copernicus University in Torun, Poland Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author (s) and source are credited. This is an open access article licensed under the terms of the Creative Commons Attribution Non commercial license Share alike. (http://creativecommons.org/licenses/by-nc-sa/4.0/) which permits unrestricted, non commercial use, distribution and reproduction in any medium, provided the work is properly cited. The authors declare that there is no conflict of interests regarding the publication of this paper. Received: 03.11.2025. Revised: 14.11.2025. Accepted: 28.11.2025. Published: 08.12.2025. UDC 616.3+615.03+612.3+577.15 FOUR STAGES AFTER STRESS REACTIONS A. P. Levitsky1, V. О. Malinovskii1, Ya. S. Yuzkiv2, K. V. Pavlenko2, I. О. Selivanskaya3, A. P. Lapinska1 1Odessa National Technological University, Odessa, Ukraine 2State enterprise Ukrainian Research Institute for Medicine of Transport, Ministry of Health of Ukraine, Odessa, Ukraine 3Odessa National Medical University, Odessa, Ukraine Abstract Stress is the main cause of non-communicable diseases. Currently, the prevailing concept is that there are two stages of post-stress reactions: the sympathetic and the neuroendocrine stages, as defined by Selye. Taking into account the ideas of nervism and in accordance with the available biochemical and pathophysiological data, we propose to consider post-stress reactions in the form of 4 stages: 1. Sympathetic. 2. Parasympathetic. 3. Neuroendocrine. 4. Dysmetabolic. At the first stage, the mediators are norepinephrine and adrenaline, at the second stage – acetylcholine, kinins, lipopolysaccharide, at the third – corticosteroids, thyroxine, at the fourth – various metabolites and microbe forums. Keywords: stress; post-stress reactions; biochemistry and pathophysiology of stress. 2 Stress arises due to various reasons (trauma, pain, intoxication, inadequate living conditions, excessive emotions) and largely determines the development of many diseases (atherosclerosis, myocardial dystrophy, neurotrophic disorders, metabolic diseases) (Table 1) [1, 2]. Тable 1. Etiological classification of human and animal diseases №№ Group of diseases Etiological factor Condition of the body 1 Infectious Pathogenic bacteria and viruses Immunodeficiency 2 Alimentary Inadequate nutrition macroorganisms and endogenous microbiota Deficiency of essential compounds in food. Hyperphagia. Dysbacteriosis . 3 Hereditary Genetic disorders Deficiency of beneficial genes. Excess of pathogenic genes. 4 Stress-induced diseases Stress Injuries, pain, intoxication, inadequate living conditions, excessive emotions Based on the principles of nervism, substantiated by I.P. Pavlov, we propose to consider stress as a chain of interconnected stages (Table 2). Post-stress reactions consist of four stages. The first stage is stimulation of the sympathetic nervous system, including the adrenal medulla. The active neurotransmitters at this stage are norepinephrine and adrenaline. The effects of catecholamines (epinephrine and norepinephrine) depend on their dose: at low concentrations, they perform a protective function, stimulating cardiovascular activity and activating hydrolytic systems (adipose tissue lipase, glycogen phosphorylase, and intravascular proteolysis). A very important property of catecholamines is the activation of free-radical oxidation processes ("oxidative stress") [3]. At high concentrations, catecholamines can cause heart attacks and strokes. 3 Тable 2. Stages of post-stress reaction development Location Syndrome Mediators Syndrome Stress Cerebral cortex, hypothalamus Acetylcholine, adrenaline, dopamine Overexcitation of the cerebral cortex Post stress reaction 1 Sympathetic Sympathetic nervous system, the adrenal medulla Norepinephrine, adrenaline Oxidative syndrome (oxidative stress) 2 Parasympathetic Parasympathetic nervous system, secretory organs Acetylcholine, kinins. Lipopolysaccharid e (LPS) Hemodynamic impairment. Increased permeability of the intestinal barrier and histohematic barriers. Dysbiotic syndrome. 3 Neuroendocrine Pituitary gland, adrenal cortex, thyroid gland ACTH, TSH, corticosteroids, thyroxine Anti-inflammatory effect. Adaptation syndrome. 4 Dysmetabolic Liver, kidneys, gastrointestinal tract, bone tissue, nervous system Elevated levels of free fatty acids, glucose, uric acid, toxins Main diseases: atherosclerosis, diabetes, obesity, NASH During the second stage of post-stress reactions, the parasympathetic nervous system (n. vagus) is activated, using acetylcholine as its active mediator. It stimulates the activity of secretory organs (primarily the salivary and gastric glands), resulting in an increase in kallikrein activity in the blood due to activation of the salivary glands. Kallikreins form kinins (bradykinin) from kininogen circulating in the blood, which significantly increase the permeability of the histohematic and intestinal barriers [4]. 4 The activity of the enzyme hyaluronidase, which is produced by the salivary glands and which causes the breakdown of hyaluronic acid (“intercellular cement”), is also activated [4]. The effect of kinins is a decrease in blood pressure and a strong increase in the permeability of the intestinal barrier, leading to the translocation of bacteria and their toxins into the bloodstream. Among microbial toxins, lipopolysaccharide (LPS) plays a special role. Our studies have shown that it possesses the highest pro-inflammatory activity, exceeding other toxic substances by hundreds and even thousands of times. The resulting dysbiotic syndrome [4] is the pathogenetic basis for many non-communicable diseases (obesity, nonalcoholic steatohepatitis, type 2 diabetes, and other metabolic diseases) [5]. The third stage of stress is the activation of the neuroendocrine system, particularly the pituitary gland, which produces hormones that act on the endocrine glands: ACTH (adrenocorticotropic hormone), TSH (thyroid-stimulating hormone), and others [1]. This stage of the post-stress response was first substantiated by G. Selye [1] and was the primary focus of research for many years. Corticosteroids, formed under the influence of ACTH on the adrenal cortex, have become firmly established in the arsenal of therapeutic anti-inflammatory agents. We propose a fourth stage in the development of post-stress reactions, manifested as dysmetabolic and immune processes in which impaired liver function plays a crucial role. In addition to its metabolic functions, the liver has antimicrobial and antitoxic functions [5]. Each stage of post-stress functions requires a selective approach to prevent its development. Thus, the first stage requires the use of antioxidants. The second stage requires the use of anti-acetylcholine drugs, antidysbiotics, and protease inhibitors (primarily kallikrein inhibitors). The third stage requires the use of agents that prevent the antimetabolite effects of corticosteroids. Finally, the fourth stage requires the use of hepatoprotectors and antitoxic agents used to treat emerging diseases. Author Contributions The authors agree to equal distribution of partial participation. Funding This study received external funding. Informed Consent Statement Informed consent was obtained from all subjects who participated in the study. Data Availability Statement 5 All information is in the public domain and specific graphic data can be obtained upon request from the corresponding senior author. Conflicts of Interest The authors declare that they have no conflicts of interest. Acknowledgments The study was carried out by the authors themselves without any outside assistance. References 1. Goldstein DS, Kopin IJ. Evolution of concepts of stress. Stress. 2007;10(2):109120. doi: 10.1080/10253890701288935. 2. Levitsky AP, Malinovskii VA. Structural classification of vitamins P. Journal of Education, Health and Sport. 2025;83:64284. https://dx.doi.org/10.12775/JEHS.2025.83.64284. 3. Reddy VP. Oxidative Stress in Health and Disease. Biomedicines. 2023;11(11):2925. doi: 10.3390/biomedicines11112925. 4. Levitsky AP. Disbiotic syndrome: etiology, pathogenesis, clinic, prevention and treatment. Dentistry Bulletin. 2019;10(special issue):14-20. (in Russian). 5. Levitsky AP, Makarenko OA, Levchenko OM [and others]. Bioflavonoid hepatoprotectors. Odessa: KP OGT, 2014:86. (in Russian).